tbuckley/cabot-search huggingface dataset:
Abstract 2578: Phosphorylation of AHR by PLK1 promotes metastasis of LUAD via upregulation of DIO2
Authors: Chaohao Li, Daheng He, Fengyi Mao, Xinyi Wang, Yanning Hao, Yifan Kong, Christine F. Brainson, Jinghui Liu, Yanquan Zhang, Ruixin Wang, Qiongsi Zhang, Zhiguo Li, Xiongjian Rao, Sai Wu, Chi Wang, Qiou Wei, Jianlin Wang, Xiaoqi Liu
Journal: Cancer Research (2023)

Abstract Non-small cell lung cancer (NSCLC) is one of the most aggressive cancer types, and metastasis of cancer cells is the major reason leading to death of patients. Aryl hydrocarbon receptor (AHR) is an important transcription factor involved in the initiation and progression of lung cancer. Polo-like kinase 1 (PLK1), a serine/threonine kinase, is another oncogene that promotes the malignancy of multiple cancer types. Preliminary examination indicates that AHR is a potential substrate of PLK1. Nonetheless, the phosphorylation and interaction of these two factors, as well as the subsequent biological significance in lung cancer remain to be determined. Here we prove that PLK1 phosphorylates AHR at serine 489 (S489) in lung adenocarcinoma (LUAD), a subtype of NSCLC. Overexpressing of exogenous AHR with mutation of phosphomemetic amino acid (S489D), enhances migration and invasion in transwell assays compared to cells harboring AHR that is unable to be phosphorylated (S489A), indicating that phosphorylation of AHR by PLK1 induces the metastatic potential of lung cancer. This is further confirmed in mouse studies using intravenous or subcutaneous inoculation of cancer cells. RNA-seq analyses of cells with S489D or S489A show that type 2 deiodinase (DIO2) is underrepresented in S489A but overexpressed in S489D. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which is the more active form of thyroid hormone and activates downstream effect. Treatment with T3 or T4 promotes the metastasis of LUAD, whereas depletion of DIO2 or treatment with deiodinase inhibitor iopanoic acid disrupts this property. Furthermore, this phenomenon is verified by in vivo mouse experiment using intravenous injection of DIO2-depleted cancer cells. Taken together, these results identify phosphorylation of AHR by PLK1 as a mechanism that leads to progression of LUAD. Citation Format: Chaohao Li, Daheng He, Fengyi Mao, Xinyi Wang, Yanning Hao, Yifan Kong, Christine F. Brainson, Jinghui Liu, Yanquan Zhang, Ruixin Wang, Qiongsi Zhang, Zhiguo Li, Xiongjian Rao, Sai Wu, Chi Wang, Qiou Wei, Jianlin Wang, Xiaoqi Liu. Phosphorylation of AHR by PLK1 promotes metastasis of LUAD via upregulation of DIO2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2578.
Abstract 725: Prostate cancer risk disparities and sociocultural factors in men of African ancestry
Authors: Joan M. Brown
Journal: Cancer Research (2023)

Abstract Introduction: The purpose of this research study was to quantify the prostate cancer (PCa) mortality rate in Men of African Ancestry (MAA) living in the State of Florida, the tri-county region of South Florida including Broward, Palm Beach, and Miami-Dade, and to explore the embodiment of sociocultural factors that contribute to the PCa disparity in the United State (U.S.). Method: A quantitative, non-experimental, descriptive study design was used to identify differences in the resident PCa mortality rate in MAA stratified based on single race of Black and birth origin of Haiti (HA), Jamaica (JA), or the United States (U.S.). The intersection of health disparities and the embodiment of chronic exposure to sociocultural stressors was also explored. Results: The Paired t-Test was used for statistical testing. The results indicated death from PCa is a health disparity in MAA in Florida when examined in aggregate by ancestry and disaggregate by birth origin. In the state of Florida, when the PCa death rate was viewed in aggregate by ancestry, a significant difference was found between MAA and Men of European Ancestry (MEA) (t(2)=4.303, p≤.01). There was a statistically significant relationship found between being MAA and death from PCa (r=.866, p≤.01). This suggests there are place based health disparities among MAA in the State of Florida. When the PCa mortality rate in MAA in the tri county region of South Florida was examined in aggregate by ancestry versus disaggregate by birth origin a significant difference was shown between MAA and HA born men (t(2)=4.30, p=0.05). No difference was shown between MAA and U.S., or JA born men. By county, the highest death rate was found in JA born men in Miami-Dade, and HA born men in Broward and Palm Beach. Overall, the lowest death rates in each county were found in U.S. born men. The results suggest that there are clear placed based and birth origin disparities in the South Florida region. Conclusions: Examining differences in the PCa mortality rates in MAA in disaggregate by birth origin provides opportunity for the observation of sociocultural factors that affect health such as cultural beliefs and fears, chronic exposure to stressors such as structural and explicit racism and racialization in the U.S, immigration status and barriers to healthcare; all sociocultural factors that if examined may aid in explaining the increased rate of PCa death experienced by MAA and why the disparity exists. Citation Format: Joan M. Brown. Prostate cancer risk disparities and sociocultural factors in men of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 725.
Abstract 1595: Thyroid hormone drives the terminal differentiation of tumor cells in medulloblastoma
Authors: Zeng-Jie Yang, Yijun Yang Yang, Allie Heller
Journal: Cancer Research (2023)

Abstract Hypothyroidism is commonly detected in patients with medulloblastoma (MB), a pediatric brain tumor, which is generally considered as a treatment-related complication. Although reduced levels of thyroid hormone (TH) significantly correlate with poor survival of patients with MB, the possible link between TH signaling and MB pathogenicity is unknown. Here, we found that TH plays a critical role in MB pathogenicity by regulating terminal differentiation of tumor cells. Elimination or reduction in the levels of TH frees the unliganded TH receptor, TRα, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives terminal differentiation of neuronal progenitors as well as MB cells. However, increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα, thereby stimulating terminal differentiation of tumor cells and reducing MB growth. Moreover, TH promotes extensive differentiation and reduced proliferation of tumor cells from multiple molecular subtypes of MB including the hedgehog (HH) group as well as group 3 (G3) MB, indicating that TH-induced differentiation is not restricted by the oncogenic driver mutations in tumor cells. Consequently, TH treatment significantly inhibits the in vivo growth of SHH- and G3-MB by promoting tumor cell differentiation, with no obvious increase in tumor cell death, indicating that TH signaling represents a novel therapeutic entry-point for broad treatment of MB. These findings elucidate the mechanisms underlying terminal differentiation of MB cells, and they establish an unprecedented association between TH signaling and MB progression. Our studies provide compelling evidence for a promising tumor therapeutic modality targeting tumor cell differentiation. Citation Format: Zeng-Jie Yang, Yijun Yang Yang, Allie Heller. Thyroid hormone drives the terminal differentiation of tumor cells in medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1595.
Abstract 6176: Enhancing treatment efficacy of glioblastoma cell lines by adding tumor treating fields (TTFields) to temozolomide and lomustine
Authors: Hila Fishman, Roni Monin, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti
Journal: Cancer Research (2023)

Abstract Background: Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cell death. Concurrent maintenance temozolomide (TMZ) with TTFields was approved by the FDA in 2014 for treatment of patients with newly diagnosed glioblastoma (ndGBM). Recently, the addition of lomustine (CCNU) to TMZ demonstrated clinical benefit in ndGBM patients. The aim of the current study was to examine in GBM cells the effect of TTFields concurrent with TMZ and CCNU. Methods: Human GBM cell lines (U-87 MG, LN229, U118, and LN18) with various MGMT expression levels were treated with TTFields (intensity of 0.83 V/cm RMS; frequency of 200 kHz) using the inovitro system. Effectiveness of TTFields concomitant with TMZ and/or CCNU was tested by measuring cell count and colony formation. Levels of DNA repair proteins in control and TTFields-treated cells were measured using Western blot. Results: The cell lines displayed different sensitivity to TMZ, in accordance with their MGMT expression level, but showed a comparable response to TTFields. TTFields concomitant with TMZ displayed an additive effect on cell numbers, irrespective of MGMT expression levels. The effect of TTFields concomitant with CCNU was additive in cell lines expressing MGMT, whereas it trended toward synergy in cell lines not expressing MGMT. Application of TTFields to the cells downregulated expression of proteins from the Fanconi Anemia-BRCA pathway for DNA repair. TTFields concurrent with both TMZ and CCNU provided higher efficacy relative to TMZ plus CCNU or TTFields apart. Conclusions: Efficacy of TMZ and CCNU may be enhanced by TTFields, with synergism seen for the latter case in cells with limited MGMT expression. The BRCAness state induced by TTFields rationalizes these outcomes, as DNA damage induced by CCNU requires the BRCA pathway for repair, especially in the absence of MGMT. The results suggest a potential benefit for concomitant TTFields with the TMZ/CCNU combination in ndGBM. Citation Format: Hila Fishman, Roni Monin, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Enhancing treatment efficacy of glioblastoma cell lines by adding tumor treating fields (TTFields) to temozolomide and lomustine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6176.
Abstract 2939: ATOR-4066, a Neo-X-Prime bispecific antibody targeting CD40 and CEA, activates myeloid cells in primary human tumors in vitro and induces anti-tumor immunity in vivo
Authors: Karin Hägerbrand, Anette Sundstedt, Mattias Levin, Yago Pico de Coaña, Laura Varas, Lill Ljung, Anneli Nilsson, Mona Celander, David Gomez Jimenez, Hampus Andersson, Malin Lindstedt, Peter Ellmark
Journal: Cancer Research (2023)

Abstract Alligator’s Neo-X-Prime platform aims to enable antigen presenting cells to efficiently enhance priming of tumor neoantigen-specific T cells. We have demonstrated that binding of a CD40 x TAA bispecific antibody (bsAb) to CD40 on dendritic cells (DCs) and a tumor-associated antigen (TAA) on tumor exosomes or tumor debris leads to activation of the DC, uptake of the tumor material, cross-presentation of a tumor-derived antigen and priming of tumor antigen-specific T cells. This has the potential to result in an increased quantity and/or quality of the tumor-targeting T cell pool and enhanced anti-tumor activity. Herein, we present ATOR-4066, a Neo-X-Prime bsAb targeting CD40 and CEA (CEACAM5), a TAA highly expressed in several cancers. Using in vitro models, we have demonstrated CEA-dependent activation of CD40-expressing cells, and an ability to mediate co-localization of CEA-expressing tumor debris and CD40 expressing antigen presenting cells. In addition, ATOR-4066 was shown to activate CD40-expressing cells in the presence of primary human tumor cells from CEA+ colorectal and gastric cancer patients. Furthermore, in vitro treatment of primary colorectal and gastric tumor-derived cell cultures and tumoroids with ATOR-4066 induced activation of tumor-infiltrating immune cells. In vivo studies using human CD40 transgenic mice bearing CEA-transfected MC38 tumors showed superior anti-tumor effects of ATOR-4066 compared to a CD40 mAb, demonstrating the ability of ATOR-4066 to efficiently induce a tumor-targeting immune response. Overall, these data show the ability of ATOR-4066 to remodel the immune microenvironment and activate tumor-infiltrating immune cells in primary human tumors expressing CEA, demonstrating the promise of this new candidate drug for further clinical development. Citation Format: Karin Hägerbrand, Anette Sundstedt, Mattias Levin, Yago Pico de Coaña, Laura Varas, Lill Ljung, Anneli Nilsson, Mona Celander, David Gomez Jimenez, Hampus Andersson, Malin Lindstedt, Peter Ellmark. ATOR-4066, a Neo-X-Prime bispecific antibody targeting CD40 and CEA, activates myeloid cells in primary human tumors in vitro and induces anti-tumor immunity in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2939.
Abstract 760: Characteristics of fatty liver disease-related hepatocellular carcinoma and genetic background in Japan
Authors: Tomomi Kogiso, Yuri Ogasawara, Kentaro Horiuchi, Makiko Taniai, Katsutoshi Tokushige
Journal: Cancer Research (2023)

Abstract Aim: A single nucleotide polymorphism (SNP) in PNPLA3 was identified as a disease susceptibility gene for fatty liver disease (FLD) and it’s associated with fibrosis progression and carcinogenesis. Additionally, mutations in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), which encodes hepatic lipid droplet protein, have been found the involvement in various metabolic processes. Loss-of-function mutations in the human HSD17B13 gene may confer a strong protective effect on liver injury, inflammation, fibrosis, and even onset of hepatocellular carcinoma (HCC). Here, we evaluated the characteristics of Japanese patients with FLD- HCC and considered the risk factors of HCC including genetic background. Methods: We enrolled 402 patients of clinically and pathologically diagnosed with FLD (alcohol: 63, nonalcohol: 339) in our hospital from 1990-2018 (228 males, median age 54.9 [14.6-83.6] years). We analyzed the survival and new-onset HCC rates according to the etiology of FLD (alcohol and nonalcohol), hepatic fibrosis, FIB-4 index, and genetic background of PNPLA3 and HSD17B13 for consideration of the risk factors. Results: FLD-HCC was observed in 57 cases (14.2%). Comparing to the patients with HSD17B13 wild-type AA (212 cases) and mutant (A/AA or AA/AA, 190 cases), patients with wild type showed significantly increased HCC complication (wild vs. mutant; 39 [18.4%] vs. 18 [9.5%], p = 0.01) and these were tended to be high complication of hypertension (120 [56.6%] vs. 90 [47.4%], p = 0.06). In patients with mutant of HSD17B13, HCC incidence was significantly reduced in alcohol-related FLD, FIB-4 index &amp;lt;2.67, and PNPLA3 CC genotype, however, there was not significant difference in nonalcohol-FLD. Patients with HSD17B13 mutant showed severe steatosis (77% vs. 88.6%). Eleven cases of new HCC were developed during observation period (8.1 [0.5-25.1] years) (n = 370). Five-year incidence of HCC was 3.3% in patients with both PNPLA3 GG/GC and HSD17B13 wild type and it was significantly elevated compared to other SNP profiles (0.6%, p = 0.03). Multivariate analysis identified the risk of FLD-HCC including age, gender, and complication of hypertension. Conclusions: Genetic background of FLD may associate with onset of HCC. Inhibiting HSD17B13 activity may prevent HCC development, especially in alcohol-related FLD and patients with low risk factors. Therefore, SNPs of gene combination with other risk factors may use for screening tool for FLD-HCC. Citation Format: Tomomi Kogiso, Yuri Ogasawara, Kentaro Horiuchi, Makiko Taniai, Katsutoshi Tokushige. Characteristics of fatty liver disease-related hepatocellular carcinoma and genetic background in Japan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 760.
Abstract 2594: Alcohol drinking inhibits NOTCH-PAX9 signaling in esophageal squamous epithelial cells
Authors: Zhaohui Xiong, Menghan Shi, Shuang Ren, Hao Chen, Jing Li, Caizhi Huang, Yahui Li, Yuning Han, Yong Li, Zheng Sun, Xiaoxin Chen
Journal: Cancer Research (2023)

Abstract Alcohol drinking has been established as a major risk factor for esophageal diseases, such as gastroesophageal reflux disease (GERD) and esophageal squamous cell carcinoma (ESCC). Certain mechanisms of alcohol-induced esophageal injury are supported by experimental data, whereas most are speculative or extrapolated from studies on cancers of other organ sites. Our previous study showed that ethanol exposure inhibited PAX9 expression in human esophageal squamous epithelial cells in vitro and in vivo, and promoted ESCC. In this study, we aimed to investigate the molecular pathways through which alcohol drinking suppresses PAX9 in esophageal squamous epithelial cells. Gene microarray, qRT-PCR, ChIP-PCR, Western blotting, and immunostaining were used to identify and validate inhibition of NOTCH-PAX9 signaling in human esophageal squamous epithelial cells and mouse esophagus after ethanol exposure. Human tissue samples were analyzed to further validate NOTCH inhibition by alcohol drinking. We first demonstrated the inhibition of NOTCH by ethanol exposure in vitro. NOTCH regulated PAX9 expression in esophageal squamous epithelial cells in vitro and in vivo. RBPJ and NOTCH intracellular domain (NICD1) ChIP-PCR confirmed Pax9 as a direct downstream target of NOTCH signaling in mouse esophagus. NOTCH inhibition by alcohol drinking was further validated in mouse esophagus and human tissue samples. In conclusion, ethanol exposure inhibited NOTCH signaling and thus suppressed PAX9 expression in esophageal squamous epithelial cells in vitro and in vivo. Our data support a novel mechanism of alcohol-induced esophageal injury through the inhibition of NOTCH-PAX9 signaling. As a result, chemical NOTCH activators may be used to prevent or treat alcohol-associated esophageal diseases such as GERD and ESCC. Citation Format: Zhaohui Xiong, Menghan Shi, Shuang Ren, Hao Chen, Jing Li, Caizhi Huang, Yahui Li, Yuning Han, Yong Li, Zheng Sun, Xiaoxin Chen. Alcohol drinking inhibits NOTCH-PAX9 signaling in esophageal squamous epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2594.
Abstract 1972: Potential predictors of prostate cancer screening: Findings from the MiCaP research digest study
Authors: Jessica Otero Machuca, Parisa Fathi, Daniel Lee, Kim Walsh-Childers, Folakemi Odedina
Journal: Cancer Research (2023)

Abstract Introduction: Black men are disproportionately affected by prostate cancer (CaP) and havebeen found to experience more aggressive forms of cancer. The Minority Prostate Cancer(MiCaP) Research Digest is a dissemination platform with the goal of spreading community-based and culturally relevant ways to provide prostate cancer discoveries, interventions, andclinical trials among Black men. In collecting pretest data, the MiCaP team was also able tocollect data on whether participants had been tested for CaP in the last year. We were also ableto collect data on various social determinant variables to test for association. Methods: Black men living in the United States ages 35 to 70 were recruited for this studythrough community-based methods. Participants were randomly assigned to an interventiongroup that received the MiCaP information material and a control group that watched a generalvideo. Both groups received baseline and follow-up surveys to assess their knowledge relatedto CaP clinical trials, testing, and treatment. Associations of characteristics from the baselinesurvey were evaluated using logistic regression models. Results: A total of 220 responses are included in this dataset. The majority of participants wereborn in the United States (93.06%), single (49.52%), attended/graduated college (35.65%),between 60 and 69 years (25.58%), had full-time employment (52.07%), and had a householdincome between 20,000 and 39,999 (21.66%). Only about 35% had read or heard about clinicaltrials within the last year. Logistic regression found a positive association between the followingvariables and getting tested for prostate cancer in the past year: if participants had heard ofcurrent prostate cancer research or discoveries, if an immediate family member had beendiagnosed with prostate cancer, age, and level of education. No association was found betweeninsurance status, utilization of healthcare, clinical trial participation, or clinical trial knowledge. Conclusion: There is an association between being aware of CaP discoveries, diagnosis of familymembers, education, and age with prostate cancer screening. Future work should be done tofurther explore this association and how to overcome the barriers those determinants mightprovide in screening. These data and future data on this can be used to further community-based interventions delivered in culturally relevant ways with the goal of encouraging positivehealth behaviors to reduce CaP in Black men. Citation Format: Jessica Otero Machuca, Parisa Fathi, Daniel Lee, Kim Walsh-Childers, Folakemi Odedina. Potential predictors of prostate cancer screening: Findings from the MiCaP research digest study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1972.
Abstract SY23-03: Rhabdomyosarcoma: New research tools for precision medicine
Authors: Corinne Mary Linardic
Journal: Cancer Research (2023)

Abstract Rhabdomyosarcoma (RMS) is a cancer of skeletal muscle histogenesis and the most common soft tissue sarcoma of childhood. Despite decades of basic and clinical research, survival for patients with high-risk disease has not improved since the 1970s, remaining &amp;lt;30% at five years. Genomic landscape studies have identified the most frequently occurring alterations, parsing out fusion-negative RMS driven by RAS pathway mutations, and fusion-positive RMS driven by signature fusion genes including PAX3-FOXO1. However, this information has not yet translated into improved outcomes. Here, we highlight multi-institutional efforts to generate new tools for RMS precision medicine, including the NCI FusOnC2 Cancer Moonshot program to target PAX3-FOXO1, the NCI CCDI Molecular Characterization Initiative to analyze every child’s RMS tumor nucleic acids, and the application of machine learning to RMS tumor images to predict molecular subtype and improve risk stratification. Citation Format: Corinne Mary Linardic. Rhabdomyosarcoma: New research tools for precision medicine. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY23-03.